chr5-73776679-A-C

Position:

• chr5-73776679-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):​c.823A>C​(p.Arg275Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,613,052 control chromosomes in the GnomAD database, including 1,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (188 hom., cov: 32)
  • Exomes 𝑓: 0.031 (882 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.58

Genes affected

ARHGEF28 (HGNC:30322): (Rho guanine nucleotide exchange factor 28) This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-73776679-A-C is Benign according to our data. Variant chr5-73776679-A-C is described in ClinVar as [Benign]. Clinvar id is 257377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73776679-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.823A>C	p.Arg275Arg	synonymous_variant	6/36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.823A>C	p.Arg275Arg	synonymous_variant	6/37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.823A>C	p.Arg275Arg	synonymous_variant	6/35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.529A>C	p.Arg177Arg	synonymous_variant	5/35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.823A>C	p.Arg275Arg	synonymous_variant	6/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6891 AN: 152138 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0325 AC: 8088 AN: 248806 Hom.: 211 AF XY: 0.0323 AC XY: 4355 AN XY: 135012

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0311 AC: 45496 AN: 1460798 Hom.: 882 Cov.: 32 AF XY: 0.0314 AC XY: 22824 AN XY: 726686

Gnomad4 AFR exome AF: 0.0842

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0488

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0454 AC: 6907 AN: 152254 Hom.: 188 Cov.: 32 AF XY: 0.0461 AC XY: 3434 AN XY: 74446

Gnomad4 AFR AF: 0.0816

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0522

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0345 Hom.: 136

Bravo AF: 0.0447

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10473959; hg19: chr5-73072504;